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| Status |
Public on Jan 30, 2019 |
| Title |
Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of aging and neurodegeneration. Here we found that, in the late-stage familial Alzheimer’s disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9Me2) and euchromatic histone methyltransferases, EHMT1 and EHMT2 (H3K9Me2 catalyzer), were significantly elevated in the prefrontal cortex (PFC) region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9Me2 at the promoter region of glutamate receptors was increased in PFC of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in PFC and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9Me2 enrichment at genes involved in neuronal signaling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.
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| Overall design |
Examination of histone H3 dimethylation at lysine 9 in wild type mice, familial AD mice and familial AD mice treated with EHMT1/2 inhibitor
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| Contributor(s) |
Zheng Y, Liu A, Wang Z, Cao Q, Wang W, Lin L, Ma K, Zhang F, Wei J, Matas E, Cheng J, Chen G, Wang X, Yan Z |
| Citation(s) |
30668640 |
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| Submission date |
Jan 29, 2019 |
| Last update date |
Mar 21, 2019 |
| Contact name |
Zhen Yan |
| E-mail(s) |
zhenyan@buffalo.edu
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| Phone |
(716) 829-3058
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| Organization name |
University at Buffalo
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| Department |
Physiology and Biophysics
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| Street address |
124 Sherman Hall
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| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14214 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA517703 |
| SRA |
SRP182834 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125850_FAD_BIX_vs_FAD_peak_compare_table.tsv.gz |
4.8 Mb |
(ftp)(http) |
TSV |
| GSE125850_FAD_vs_WT_peak_compare_table.tsv.gz |
3.8 Mb |
(ftp)(http) |
TSV |
| GSE125850_README_Compare.txt |
658 b |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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